An fMRI study of reduced left prefrontal activation in schizophrenia during normal inhibitory function

Schizophrenia Research 52 (2001) 47±55

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An fMRI study of reduced left prefrontal activation in schizophrenia during normal inhibitory function Katya Rubia a,*, Tamara Russell a, Edward T. Bullmore b, William Soni a, Mick J. Brammer a, Andrew Simmons a, Eric Taylor a, Chris Andrew a, Vincent Giampietro a, Tonmoy Sharma b a

Departments of Child Psychiatry, Psychological Medicine, and Neurology, Institute of Psychiatry, King's College, De Crespigny Park, London, SE5 8AF, UK b Department of Psychiatry, Addenbrooke's Hospital, University of Cambridge, UK Received 24 July 2000; accepted 11 October 2000

Abstract Functional magnetic resonance imaging (fMRI) was used to investigate the hypothesis that schizophrenia is associated with a dysfunction of prefrontal brain regions during motor response inhibition. Generic brain activation of six male medicated patients with schizophrenia was compared to that of seven healthy comparison subjects matched for sex, age, and education level while performing `stop' and `go-no-go' tasks. No group differences were observed in task performance. Patients, however, showed reduced BOLD signal response in left anterior cingulate during both inhibition tasks and reduced left rostral dorsolateral prefrontal and increased thalamus and putamen BOLD signal response during stop task performance. Despite good task performance, patients with schizophrenia thus showed abnormal neural network patterns of reduced left prefrontal activation and increased subcortical activation when challenged with motor response inhibition. q 2001 Elsevier Science Ltd All rights reserved. Keywords: fMRI; Schizophrenia; Anterior cingulate; Dorsolateral prefrontal cortex; Thalamus; Basal ganglia; Putamen; Response inhibition; Stop task; Go-no-go task; Frontal lobes; Executive functions

1. Introduction The pathophysiology of the heterogeneous disorder of schizophrenia is still unresolved. Although genetic factors play a substantial role, single causative genes have not yet been identi®ed (Pulver, 2000), and neurochemical and neurodevelopmental processes are still under investigation (Harrison, 1999). Structural studies have found differences in frontal and temporal * Corresponding author. Tel.: 120-7-848-0463; fax: 120-7-7085800. E-mail address: [email protected] (K. Rubia).

regions, the ventricles and subcortical brain regions (Wright et al., 2000). It is possible that frontal lobe abnormalities in schizophrenia are due to functional pathology rather than to a structural dysmorphism. Functional neuroimaging is therefore likely to be one of the most suitable tools of investigation for schizophrenia research. Normalization of functional hypofrontality after symptomatic improvement has indeed been shown (Spence et al., 1998). Hypofrontality in schizophrenia appears to be task-speci®c; it has mainly been found during executive task performance (for overview see: Chua and McKenna, 1995; Velakoulis and Pantelis, 1996), but rarely during rest

0920-9964/01/$ - see front matter q 2001 Elsevier Science Ltd All rights reserved. PII: S 0920-996 4(00)00173-0

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(Chua and McKenna, 1995; Andreasen et al., 1992) nor during non-executive tasks involving memory or semantic processes (Ragland et al., 1998; Curtis et al., 1999). The aim of this study was to extend the search for task-speci®c hypofrontality in schizophrenia using fMRI. We hypothesized that patients with schizophrenia would show reduced frontal activation to response inhibition paradigmsÐgo-no-go and stop tasksÐ which have shown to activate medial, dorsal and inferior frontal brain regions in healthy subjects (Rubia et al., 2001a). 2. Methods and materials 2.1. Subjects Six clinically referred right-handed patients diagnosed with schizophrenia (DSM IV; American Psychiatric Association, 1995), aged 26±57 years (mean age ˆ 40, SD ˆ 9), with mean intelligence quotient (IQ) higher than 80 (Quick Test, Ammons and Ammons, 1962) participated in the study. Patients were taking atypical antipsychotic medication. Duration of illness was 5±28 months (mean ˆ 15.7, SD ˆ 9.3 months), mean onset of illness was 20±30 years (mean ˆ 24, SD ˆ 4). Controls were seven adults, matched for years of education (controls ˆ 16 years, SD ˆ 5, patients ˆ 12 years, SD ˆ 3) and socio-economic status to avoid pre-morbid IQ differences (O'Carroll et al., 1992), handedness and age (26±58 years; mean age ˆ 40, SD ˆ 11), who had no personal or family history of psychiatric disorder. Subjects in either group with a history of drug abuse in the 6 months prior to scanning or neurological disorder were excluded. The study was approved by the local Ethical Committee. 2.2. Experimental design Throughout image acquisition, each subject's performance was monitored by a right-handed button press and recorded by means of a MR compatible interface to a PC. The order of the computerised task presentation was counterbalanced. Each paradigm consisted of two main conditions (activation and control condition), lasting for 27 s, preceded by a short visual warning cue (3 s). Control and activa-

tion condition epochs (30 s each) were periodically alternated ®ve times in the course of a single experiment lasting 5 min. Stop task: in the control condition, an airplane pointing to the right appears on the screen (Inter-Stimulus-Interval (ISI) 1650 ms; duration of airplane 1000 ms, 650 ms blank screen; 18 stimuli per epoch). On 30% of trials the airplane pointing to the right is followed 250 ms later by an airplane pointing to the left (300 ms duration), and is then followed by a blank screen for 1100 ms. The subject is required to press a button whenever an airplane pointing to the right appears, whether or not it is followed by the second airplane. The activation condition is identical to the control condition, but instead of the airplane pointing to the left a bomb appears in 30% of trials, 250 ms after onset of the airplane. The subject is instructed to press the button if the airplane is not followed by the bomb, and not to press the button if the airplane is followed by the bomb (Rubia et al., 1999, 2000, 2001a,b). The task matches for the number of stimuli but not completely for the number of motor responses, which was slightly reduced in the inhibition condition (by about four responses). GoNo-Go task:in the control condition, airplanes pointing either to the right (70%) or the left (30%) appear on the screen (ISI ˆ 1.3 s). Subjects are instructed to press a response button as quickly as they possibly can after seeing either airplane. In the activation condition, bombs appear instead of the airplanes pointing to the left in 30% of trials (ISI ˆ 1 s). Subjects are instructed to press a response button after seeing the airplanes but not after seeing the bombs. This design controls for the number of motor responses, but not completely for the number of visual stimuli, which was slightly increased in the activation condition (by four stimuli) (Rubia et al., 2001a). 2.3. Image acquisition Gradient-echo echoplanar MR images were acquired using a 1.5 Tesla GE MR Signa System ®tted with Advanced NMR hardware and software at the Maudsley Hospital, London. A quadrature birdcage head coil was used for RF transmission and reception. In each of 14 non-contiguous planes parallel to the anterior-posterior commissure, 100 T2*-weighted MR images depicting blood-oxygenation-level-dependent (BOLD) contrast (Ogawa et al., 1990) were acquired

K. Rubia et al. / Schizophrenia Research 52 (2001) 47±55

with TE ˆ 40 ms, TR ˆ 3000 ms, ¯ip angle ˆ 908, inplane resolution ˆ 3.1 mm, slice thickness ˆ 7 mm, slice-skip ˆ 0.7 mm. In the same session, a 43 slice, high resolution inversion recovery echoplanar image of the whole brain was acquired in the intercommissural plane with TE ˆ 40 ms, TI ˆ 180 ms, TR ˆ 16,000 ms, in-plane resolution ˆ 1.5 mm, slice thickness ˆ 3 mm, slice-skip ˆ 0.3 mm. 2.4. Image analysis Methods used for fMRI time series analysis, randomisation process and the necessary treatment of autocorrelation have been described elsewhere in detail (Bullmore et al., 1996; Brammer et al., 1997). The standardised power (FPQ) of periodic signal change at the frequency of alternation between control and activation conditions was estimated by ®tting a sinusoidal regression model, using an iterated least squares procedure, to the movement-corrected time fMRI series at each voxel (Bullmore et al., 1999a). The movement correction method (Bullmore et al., 1999a) calculates the change in the activation statistic (FPQ) caused by motion correction and then uses this at a group level to correct for inter-subject differences. At this stage correction is made for both stimulus correlated and non-stimulus correlated motion. The sign of gamma indicated the phase of periodic signal change with respect to the input function. Maps were constructed to represent FPQ and gamma at each voxel of each observed dataset. Each observed time series was randomly permuted 10 times at each voxel, and FPQ estimated as above in each randomized time series, to generate 10 permuted maps of FPQ for each subject in each anatomical plane. The random permutation destroys the relationship between the experimental paradigm and the response at that voxel and thus computes FPQ under the appropriate null hypothesis. This randomisation process and the necessary treatment of autocorrelation, is described in detail in Bullmore et al. (1996). The technique is widely used to remove the necessity for any assumption regarding the form of the distribution of a statistic under the null hypothesis by computing that distribution directly from the data itself. To construct generic brain activation maps, all observed and permuted FPQ maps were transformed into the standard space of Talairach and Tournoux and smoothed by a 2D Gaussian ®lter (SD ˆ 3.0 mm)

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(Talairach and Tournoux, 1988). The median value of FPQ at each intracerebral voxel in standard space was then tested against a critical value of the permutation distribution for median FPQ ascertained from the permuted FPQ maps. For a one-tailed test of size a ˆ 0.0023 (allowing for 50 error voxels over the 16 slices), the critical value was the 100 £ (1 2 a )th percentile value of the permutation distribution. Maps of g observed in each individual were likewise transformed into standard space and smoothed and voxels generically activated in phase with the activation condition as determined by the median value of g were coloured and superimposed on a grey scale template image to form a generic brain activation map (Bullmore et al., 1999b). Between group differences in activation were estimated by ®tting a one-way analysis of covariance (ANCOVA) model at each voxel, with IQ as the covariate, to generate a map of the main effect of group at each voxel. This map was thresholded (with two-tailed voxel-wise P , 0.05) to generate a set of spatially contiguous 3D clusters of suprathreshold voxel statistics and the sum of suprathrehold voxel statistics in each cluster was tested against its sampled permutation distribution under the null hypothesis of zero group effect with one-tailed cluster-wise P , 0.01 (see Bullmore et al., 1999b, for details). The rationale for this procedure is that spatially informed test statistics in functional imaging are generally more sensitive than voxel statistics, and the number of tests to be conducted at cluster level is generally fewer than the number required at voxel level, yet theoretical approximations for null distributions of spatial statistics are often over-conservative or intractable. The adoption of a computational inference procedure, however, allows valid hypothesis testing on the basis of spatially informed test statistics, which means that the number of false positive tests can be minimised without undue loss of sensitivity or restricting a priori the search volume for betweengroup testing to a subset of the brain.

3. Results 3.1. Behavioural data Differences were observed in mean IQ (controls:

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Table 1 ANCOVA with IQ as covariate. Means after adjusting for IQ deviation score differences. P ˆ probability level, PI ˆ probability of inhibition, SD ˆ intra-subject standard deviation Task

Measure

Controls Mean(SD)

Patients Mean (SD)

ANCOVA F(df ˆ 1)

P , 0.05

Go-no-go

PI MRT SD PI MRT SD

90(3) 294(68) 87(31) 94(5) 605(111) 147(31)

88(3) 314(75) 120(19) 92(6) 533.6(95) 143(30)

0.07 0.15 0.16 0.47 1.0 0.04

0.79 0.70 0.16 0.50 0.34 0.84

Stop

117, SD ˆ 15, schizophrenic patients: 101, SD ˆ 4, two-tailed t-test, t ˆ 22.57, df ˆ 11, P , 0.028). Multivariate analysis of variance (ANCOVA) with group as dependent measure and IQ as covariate showed no group differences in task performance in any of the dependent variables (see Table 1). 3.2. Imaging data Since high stimulus and non stimulus-correlated motion in patients with schizophrenia can present an artifact on functional group activation data (Callicott et al., 1998), we compared these measures between groups. No group differences were observed in stimulus correlated motion in any of the tasks, calculated as the average extent of rigid body motion in x, y and z translations as well as pitch, roll and yaw (Gonogo: controls: 1.14 ^ 0.5, patients: 1.15 ^ 0.7, df ˆ 11, t ˆ 20.02, P , 0.9; Stop: controls: 0.99, patients: 0.89, df ˆ 11, t ˆ 0.5, P , 0.6), nor in the maximum extent of the largest movement (regardless of stimulus-correlation) in x, y, and z (Gonogo: controls: 0.35 ^ 0.28, patients: 0.36 ^ 0.17, df ˆ 11, t ˆ 20.107, P , 0.916; Stop: controls: 0.25 ^ 0.20, patients: 0.34 ^ 0.19, df ˆ 11, t ˆ 0.86, P , 0.4). 3.2.1. Stop task Generic activation in controls during the stop condition (P , 0.0023) was in bilateral anterior cingulate (Brodmann Area (BA) 32/9/10; Talairach Coordinates in mm x/y/z: right: 0/44/22; 51 voxels, left: 26/39/20; 10 voxels), bilateral inferior frontal cortex (BA 44; right: 6/219/37; 16 voxels, left: 52/ 6/9; 11 voxels), and right cerebellum (6/264/27; 12 voxels). Generic activation in patients with schizophrenia

during the stop condition was in right inferior frontal cortex (BA 44/47, 52/11/4; 48 voxels), predominantly right inferior parietal lobe (BA 40; 3/253/20; 35 voxels), right precentral gyrus (BA 6, 29/28/42; 14 voxels), thalamus (0/211/4; 19 voxels), right putamen (29/3/22; six voxels), right anterior cingulate (BA 24; 3/25/31; seven voxels) and right cerebellum (14/250/213; six voxels). For the ANCOVA analysis the number of positive clusters tested was 226 and the cluster-wise probability of a false positive test was P , 0.01. We observed differences at three voxel clusters. Reduced signal response in patients with schizophrenia was observed in predominantly left anterior cingulate (BA 32/10) and left rostral dorsolateral superior frontal gyrus (BA 9). Increased activation was observed in right and left dorsomedial and ventrolateral thalamus, predominantly right putamen and the interface between right precentral gyrus and right insula (Fig. 1, Table 2). 3.2.2. Go-no-go task Generic activation in controls during the go-no-go condition was in left pre- and postcentral gyrus (BA 6/ 1/2/3/4; Tal. coord. 240/228/42; 90 voxels), predominantly right SMA (BA 6; 3/0/59, 55 voxels), predominantly left inferior parietal lobe (BA 40; 240/244/ 42, 60 voxels), left precuneus (BA 7; 29/258/37, 38 voxels) and posterior cingulate (BA 7/31, 0/261/9, 20 voxels), bilateral inferior prefrontal lobe (BA 45, right: 55/11/9, 11 voxels; left: 232/17/20; 22 voxels), left middle frontal lobe (BA 46; 229/36/26; 23 voxels, anterior cingulate (BA 24/32; 3/26/42; 24 voxels), and left middle temporal lobe (BA 21; 252/250/9, 23 voxels). Patients with schizophrenia showed activation in

K. Rubia et al. / Schizophrenia Research 52 (2001) 47±55 Fig. 1. ANCOVA map showing signi®cant between group differences of 3D suprathreshold voxel-clusters at P , 0.01; yellow voxels show greater signal intensity in comparison subjects, while blue voxels show greater signal intensity in schizophrenic patients.

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Table 2 Main brain regions differentially activated in subjects with schizophrenia (S) and in healthy controls (C) during performance of stop and go-nogo tasks Task/Cerebral region StopTask L anterior cingulate L superior frontal gyrus R Thalamus R Putamen Go-No-Go task L anterior cingulate a

BA a

Talairach Coord. (x, y, z)

Volume(3D; nr. voxels)

Between group differences

32/10 9/6

2 5;42;18 2 27;8;61 14; 2 7;9 22; 2 2; 2 4

302 113 458 102

C.S C.S S.C S.C

32/24

2 5;40;7

177

C.S

BA ˆ approximate Brodmann Area.

left and right superior parietal cortex (BA 7/40; left: 214/250/53, 43 voxels; right: 32/53/48; 45 voxels), in posterior cingulate (0/236/42; 18 voxels), and in inferior temporal lobe (BA 47; 40/261/27; nine voxels). For the ANCOVA analysis the number of positive clusters tested was 226 and the cluster-wise probability of a false positive test was P , 0.01. We observed differences at one voxel cluster. Reduced signal response in schizophrenic patients was in predominantly left anterior cingulate (BA 32/24). (see Table 2, Fig. 1). 4. Discussion Despite equivalent performance in both response inhibition paradigms, patients showed reduced BOLD signal response in left anterior cingulate during both go-no-go and stop tasks. During the stop task, patients showed in addition reduced activation in left superior frontal gyrus and increased activation in right thalamus and right putamen. Response inhibition tasks have mostly been used in child psychiatry, where they elicit impairment in subjects with impulsivity traits such as aggressive or hyperactive children, but not in children with other psychiatric diagnoses (Rubia et al., 1998a, 2001b). Although the small sample size limits the interpretability of the ®ndings, motor response inhibition seems not be one of the cognitive executive dysfunctions of schizophrenic disorder. Inhibitory de®cits in schizophrenia may thus be limited to the verbal domain (Chua and McKenna, 1995; Baxter and Liddle, 1998) and to

early attentional sensory stages (McDowd et al., 1993; Abel et al., 1992; Fukushima et al., 1994; Fuller et al., 2000) rather than the motor level. Our ®ndings add to other positron-emission tomography (PET) and fMRI ®ndings of predominantly left hemispheric anterior cingulate and dorsolateral hypofrontality in patients with schizophrenia when challenged with an executive `frontal' task (Andreasen et al., 1992, 1997; Weinberger et al., 1996; YurgelinTodd et al., 1996; Carter et al., 1997) and of reduced fronto-central electrophysiological activity during gono-go task performance (Weisbrod et al., 1999). Reduced activation of anterior cingulate and prefrontal gyrus may be the functional correlate of structural abnormalities in these brain regions (for overview see Wright et al., 2000). Although anterior cingulate has been found to be activated during go/no-go and stop tasks (Rubia et al. 1999, 2000, 2001a), it has been attributed a more general meta-motor attentional control function, including motor attention, response selection (Devinsky et al., 1995; Rubia et al., 1998b, 1999) and monitoring response competition (Carter et al., 1998, 1999a; Botvinick et al., 1999). All of these functions are necessary to perform inhibition tasks. In line with the meta-motor attentional control aspect of anterior cingulate is the fact that reduced anterior cingulate has been found in schizophrenia during other executive tasks (Fletcher et al., 1999; Carter et al., 1999b; Cohen et al., 1998). It would also explain the apparent paradox of underactivation with normal performance, since underactivation in anterior cingulate and dorsolateral prefrontal cortex, compromising general motor attention, may not have been suf®cient to impair speci®c inhibitory performance.

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It has been debated by some authors that functional hypofrontality in schizophrenia may be an artefact of poor task performance (Weinberger and Berman, 1996; Frith, 1996). Here we observed reduced frontal signal during equivalent task performance. Although uncommon, this has been observed by other authors during working memory (Weinberger et al., 1996), verbal recall (CrespoFacorro et al., 2000) and sustained attention (Cohen et al., 1998; Volz et al., 1999). Poor task performance alone can therefore not account for reduced frontal activation in patients with schizophrenia. The ability to compensate with alternative neurocognitive activation routes, such as hyperactivation of basal ganglia and thalamus during the stop task, may have been responsible for successful performance in patients despite localized de®cits in frontal activation. Abnormalities in fronto-striato-thalamic circuits have been hypothesized to underlie the cognitive de®cits in schizophrenia (Frith and Done, 1988; Andreasen et al., 1997). This is supported by recent imaging studies of reduced thalamic volume (Hazlett et al., 1999;Sachdev and Brodaty, 1999; Ettinger et al., 2000) and activation (Crespo-Facorro et al., 2000). This is supported by recent imaging studies of reduced thalamic volume (Hazlett et al., 1999;Sachdev and Brodaty, 1999; Ettinger et al., 2000) and reduced activation (Crespo-Facorro et al., 2000). The relationship between size and function seems not to be linear, as other functional studies observed, like this one, hypoactivation in prefrontal brain regions in conjunction with `hyperactivation' in thalamus and putamen (Andreasen et al., 1997; Cohen et al., 1998; Kim et al., 2000). In a recent developmental study we showed reduced activation in left dorsal and ventrolateral prefrontal brain regions and increased activation in right hemispheric subcortical structures (insula and basal ganglia) in adolescents compared to adults during comparable performance of the same stop task (Rubia et al., 2001a), which could be supportive of the neurodevelopmental hypothesis of schizophrenia (Harrison, 1999). The decrease in left prefrontal activation is in line with theories of hemispheric imbalance of schizophrenia (Gur and Chin, 1999; Gruzelier, 1999) and shows an interesting contrast to a reduced right prefrontal pattern in the externalizing

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disorder of ADHD during the same stop task (Rubia et al., 1999, 2001a,b). A confounding factor in our study is the fact that patients were medicated. A bifurcated effect of region-speci®c reduction and increase of the BOLDsignal would, however, be dif®cult to explain if a globally disruptive medication effect was hypothesized. Previous studies have shown that schizophrenic patients were as likely to be hypofrontal during executive tasks whether medicated, medication-free or neuroleptic-naive (Andreasen et al., 1992; Rubin et al., 1991; Kim et al., 2000). We are aware that the small sample size limits the generalizability of ®ndings. Further studies using larger numbers of subjects, with symptomatic subgroups, are necessary to corroborate and specify these ®ndings of abnormal activation pattern during inhibitory challenge. In summary, fMRI was used to investigate the hypothesis of reduced signal response in frontal brain regions in patients with schizophrenia during two response inhibition tasks. Despite good task performance, schizophrenic patients showed reduced signal response in mesial prefrontal brain regions during inhibition on both tasks and increased subcortical activation during stop task performance. Acknowledgements This work was supported by a donation from Grosvenor Group plc and Psychmed Ltd. Dr Bullmore was supported by the Wellcome Trust. References Abel, L.A., Levin, S., Holzman, P.S., 1992. Abnormalities of smooth pursuit and saccadic control in schizophrenia and affective disorders. Vision Res. 32 (6), 1009±1014. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, DSM-IV. 4th ed. American Psychiatric Press Inc, Washington, DC. Ammons, R., Ammons, C., 1962. Quick Test. Psychological Test Specialists, Missoula, MT. Andreasen, N.C., Rezai, K., Alliger, R., Swayze, V.W., Flaum, M., Kirchner, P., Cohen, G., O'Leary, D.S., 1992. Hypofrontality in neuroleptic-naive patients and in patients with chronic schizophrenia. Assessment with xenon 133 single-photon emission computed tomography and the Tower of London. Arch. Gen. Psychiatry 49 (12), 943±958.

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